The field of invention is the treatment of erectile dysfunction. In particular, the subject matter of this invention consists of a novel and effective treatment of erectile dysfunction using an agent or agents with actions which combine the properties of (a) preventing the induction of pain and (b) reducing the potential for priapism with enhanced capacity for corpus cavernosal smooth muscle relaxation (penile erection).
Erectile dysfunction (ED) is a significant clinical problem which occurs in up to thirty percent of males in North America. Causes of impotence are usually divided into two nonexclusive categories, namely, organic and psychological. Organic aspects of ED are typically caused by underlying vascular disease such as that associated with hypertension or diabetes mellitus, can be caused by prescription medications and may include psychiatric disease such as depression. Psychological factors include fear, performance anxiety and interpersonal conflict. ED impairs sexual performance, diminishes self-esteem and disrupts personal relationships (Padma-Nathan, et al NEJM, Vol. 336 (1):1, 1997).
The human male penis is composed of erectile tissue called the corpus cavernosum and corpus spongiosum. The corpus cavernosum is comprised of two segments or erectile bodies each located adjacent to the urethra (or the corpus spongiosum). The erectile tissue is composed of large venous sinuses which contain relatively little blood when the penis is not in the relaxed state but which become very engorged by blood when dilated (relaxed). The dilation of these tissues contributes directly to penile erection.
The stimulus for a physiological erection originates in the central nervous system. A fully functional natural penile erection requires co-ordinated change in output from various levels of the central nervous system and at least three sets of peripheral nerves (thoracolumbar sympathetic, sacral parasympathetic, and pelvic somatic). At the level of penile tissue, localization of sympathetic and parasympathetic as well as non-adrenergic, non-cholinergic nerve terminals has indicated the potential involvement of numerous neurotransmitter systems. A penile erection is known to be dependent upon the balance and integration between structural (vascular and extracellular matrix) and functional control systems (neural, local factors and humoral/endocrine). The nature of the balance between these contributing influences is ultimately expressed as vasodilation and penile tumescence, as long as there is an adequate level of systemic blood pressure and an appropriate hormonal milieu. The penile vascular components that have a significant role in regulating erectile function are the pudendal arterial system, the cavernous arteries, the corpora cavernosa and the corpus spongiosum and glans.
It is well established that an erection requires a neurally mediated (autonomic) vasodilation of both the penile arterial blood vessels and the trabecular meshwork. The combined dilatation facilitates an initial rapid increase in arterial inflow into the cavernous bodies of the penis, promoting tumescence. This is followed by a phase of decreasing inflow as the corporal tissue expands and compresses sub-tunical veins. This is described as the xe2x80x9cveno-occlusive mechanismxe2x80x9d, and this imposes a dramatic increase in inflow resistance which is required to achieve penile rigidity. Conversely, detumescence is likely mediated, at least in part, by activation of the sympathetic nervous system as well as removal of active vasodilator tone. In addition, it may involve changes in local systems.
One of the widely accepted interventions used in the diagnosis and pharmacological management of erectile dysfunction involves direct injection of a wide range of vasoactive substances into the corpus cavernosum (penis) for the purposes of producing an erection (intra cavernosal xe2x80x9cICxe2x80x9d injections). Newer strategies involve the delivery of a similar range of drugs to the urethra (then to the corpus cavernosum by natural mechanisms) with similar consequences. The currently accepted injectable products are not optimal. Two serious adverse reactions associated with these agents are drug-induced pain and priapism (i.e., erections of inappropriate overlong duration) (Linet et al, NEJM, Vol. 334:873 (1996)). It is now known and has been documented in the literature that a single use of prostaglandin E1 (PGE1) produces a pain response in about 3 to 10 percent of individuals using this therapy. However, it also known that over time the repeated use of PGE1 is associated with a continuing incidence of pain. This is such that 40 to 45 percent of patients using PGE1 multiple times will report a pain response with use (Linet et al, NEJM, Vol 334 (14) 873 (1996)). When such patients use PGE1 for a prolonged period of time, they expect that they may experience pain and this becomes a serious problem which may result in decreased use of PGE1 or switching to an alternative therapy. Alternatives currently include surgical intervention (destructive and irreversible, with a success rate between 31 to 80 percent); vacuum devices (moderate efficacy, may be difficult for some men to use and may cause penile trauma); and oral medications (unproven efficacy). Transurethral administration of PGE1 or other vasoactive agents is another alternative approach to injection therapy, although it has resulted in report of penile pain in 35.7 percent of men who attended for clinic testing (Padma-Nathan et al, NEJM, Vol. 336(1): 1 (1997)). At present it is our understanding only two products are approved by the United States FDA for the treatment of ED: intracavernosal injection using PGE1 (Caverject, Upjohn Pharmaceutical; Virilan, Schwarz Pharma) and intraurethral PGE1 (MUSE, Vivus Inc. Menlo Park, Calif.). Thus there is a need to provide a method or therapy for inducing effective erections (and avoid priapism) while reducing or entirely avoiding pain.
The present invention is a therapy in which the combination of actions of an agent or agents induce effective erections (and avoid priapism) while reducing or entirely avoiding pain.
According to one aspect of the present invention there is provided a method of augmenting the actions of cyclic adenosine monophosphate (cAMP) in an effector system while reducing cAMP action in a nociceptive system which method comprises application of one or more of the various forms of NO, or CO, to a site wherein the said cAMP exists.
According to another aspect of the present invention, a method is provided wherein alteration of the actions of cAMP is caused by application of an agent which increases cyclic guanosine monophosphate (cGMP).
According to another aspect of the present invention, a method is provided wherein alteration of the actions of cAMP is caused by application of an agent which inhibits phosphodiesterase.
In yet a further aspect of the present invention there is provided, in an anatomical site where nociceptive tissue is in close proximity to one or more effector systems, a method for enhancing said effector system while reducing nociception in said nociceptive tissue comprising modifying the actions of cAMP at said site by application of one or more of the various forms of NO or CO, or comprising application of an agent or agents that potentiate or augment the action of cAMP in said effector systems and in said nociceptive tissue, causing an increase of cGMP relative to cAMP, which would include an overall reduction in cAMP but with relatively more cGMP. The penis and clitoris are examples of such anatomical sites.
According to one aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain by use of one or more agents that can augment or potentiate the effect of cAMP as well as augment or potentiate the effect of cGMP in both smooth muscle and nerves, irrespective of whether the effect is mediated by changes in the adenylyl or guanylyl cyclase systems or by direct action of NO or CO, or the cyclic nucleotide phosphodiesterases which inactivate these cyclic nucleotides.
According to yet a further aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain by use of an agent which directly or indirectly generates NO and which augments or potentiates the effect of cAMP in smooth muscle but not in nerves.
According to a further aspect of the present invention there is provided a method for enhancing penile erection with minimal or no pain by use of an agent which generates NO in both smooth muscle and nerves in combination with an agent that augments or potentiates the effect of cAMP in smooth muscle but not in nerves.
According to yet a further aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain by use of any one of the following NO donors: gylceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosydnonimine molsidomine, S-nitroso-N-acetylpenicillamine, Snitrosoglutathione, N-hydoxy-L-arginine, S,S-dinitrosodithiol, or NO gas, or a functional equivalent thereof in combination with an agent that augments or potentiates the effect of cAMP in smooth muscle but not in nerves.
According to a further aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain by use of one or more agents which generate NO or CO and which augment or potentiate the effect of cAMP in smooth muscle but not in nerves.
According to a further aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain by use of an agent which generates NO in both smooth muscle and nerves in combination with an agent that augments or potentiates the effect of cAMP in smooth muscle but not in nerves.
According to a further aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain by use of at least any one of the following NO donors: glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosydnonimine molsidomine, S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione, N-hydroxy-L-arginine, S,S-dinftrosodithiol, or NO gas, or functional equivalents thereof, in combination with an agent that augments or potentiates the effect of cAMP in smooth muscle but not in nerves.
According to a further aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain by use of any one of the following NO donors: glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosydnonimine molsidomine, S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione, N-hydroxy-L-arginine, S,S-dinitrosodithiol, or NO gas, or functional equivalents thereof, in combination with PGE1 or other prostaglandin.
In yet a further aspect of the present invention there is provided a method of enhancing penile erection with minimal or no pain whereby these agents are delivered by any route that will affect penile smooth muscle.
It is a further aspect of the present invention that the methods of this invention are not specific to the penis in that the mechanism is relevant to other systems where avoidance of nociception and enhancement of efficacy are important. For example, regional or generalized pain managed by opiates would be offset by addition of NO generating or active (single agent or combined) compounds that alter relative cAMP and cGMP activation.
The pain reduction of the present invention is hypothesized to result from two independent events which involve actions in two different cellular systems (nerves and smooth muscle). Our idea is to combine a first action which is to antagonize the drug-induced pain stimulus within nociceptive nerves and a second action which is to enhance, synergistically, smooth muscle relaxation. This synergism allows for at least an equivalent effect to be obtained at significantly lower doses of the pain-inducing agent (e.g. PGE1) again reducing the potential for pain.
We further expect that the novel therapeutic strategy of the present invention results in a decrease in pain induced by cAMP elevating agents (e.g. PGE1). We believe that this is accomplished by the antinociceptive actions of increases in levels of cGMP and or NO and or CO and or relative activities in cAMP and cGMP systems in nociceptive nerves mediated by the second agent (or by a second action of the same agent (Ferreira et al, European Journal of Pharmacology 201:121 (1991)). We believe that the combined actions of agent(s) which simultaneously increase both cAMP and cGMP and appear therefore to result in synergistic enhancement in the smooth muscle in those studies, also result in synergistic enhancement of the corpus cavernosal relaxation and hence the erectile response. Note however that the combined actions of the agent(s) in the two tissues are in direct contrast: in nerves the effects of cGMP are antagonistic to the actions of cAMP while in smooth muscle cGMP directly potentiates the effects of cAMP. Notwithstanding this, surprisingly in corpus cavernosal tissue no pain has been observed with such combinations.
A specific example of this invention, described herein, includes the use of a combination of an agent which activates the adenylyl cyclase system (PGE1) and an agent which can both activate the guanylyl cyclase system (sodium nitroprusside-SNP) as well as other systems acting independently of guanylyl cyclase. Alone each of these agents causes smooth muscle relaxation. PGE1 alone, at concentrations which cause smooth muscle relaxation, also can induce hyperalgesia (i.e. pain in approximately 40-45% of patients causing discontinuation of use). SNP injected alone into the penis appears not to induce pain but at doses required to produce consistent penile erections does suffer from a serious side effect of unacceptable systemic hypotension. Typical clinically effective doses for PGE1 monotherapy are between 5 and 20 xcexcg. SNP alone has been shown to produce inadequate penile erections at doses of 50 xcexcg whereas approaching 200 xcexcg it will induce erections but with the significant systemic side effects (Brock et al J. Urology, Vol. 150:864, 1993). We demonstrate below, use of a low dose (5 xcexcg) or moderate dose (15 xcexcg) of PGE1 combined with a low dose SNP (50 xcexcg) to achieve effective erection with no pain.
GTN=glyceryl trinitrate
ISMN=isosorbide 5-mononitrate
ISDN=isosorbide dinitrate
PETN=pentaerythritol tetranitrate
ETN=erythrityl tetranitrate
SNP=sodium nitroprusside
SIN-1=3-morpholinosydnonimine molsidomine
SNAP=S-nitroso-N-acetylpenicillamine
SNOG=S-Nitrosoglutathione
NOHA=N-hydroxy-L-arginine
PDE3=phosphodiesterase type III
PGE1=prostaglandin E1
cAMP=cyclic adenosine monophosphate
cGMP=cyclic guanosine monophosphate
T=Tumescence
R=Rigidity
xe2x80x9cPenisxe2x80x9d as used herein may be interpreted to apply equally to clitoris in so far as there is substantial equivalence between penile and clitoral erectile tissue.
xe2x80x9cEnchancing penile erectionxe2x80x9d as used herein is understood to mean increasing physical size and improving rigidity of a penis.
xe2x80x9cErection of good qualityxe2x80x9d and xe2x80x9ceffective erectionxe2x80x9d are used herein interchangeably to mean adequate for vaginal penetration (i.e., intromission, or intercourse).
xe2x80x9cPDE3xe2x80x9d and xe2x80x9cPDEIIIxe2x80x9d are used interchangeably to describe the phosphodiesterase type three which normally degrades cAMP and is inhibitable by cGMP.
xe2x80x9cNO donorxe2x80x9d and xe2x80x9cNOxe2x80x9d producing agent"" are used interchangeably in this specification and include all compounds which donate NO through biotransformation, compounds which generate NO spontaneously, compounds which spontaneously release NO, or any other compounds which otherwise generate NO.
xe2x80x9cvarious forms of NOxe2x80x9d as used herein is understood to mean any one of NO, xe2x88x92NO+ and NOxe2x88x92, and can include as an alternative CO (carbon monoxide).
xe2x80x9capplying various forms of NOxe2x80x9d as used herein includes NO donor or NO producing agents